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【转帖】细胞碉亡信号途径

Apoptosis is a naturally occurring process by which a cell is directed to Programmed Cell Death. Apoptosis is based on a genetic program that is an indispensable part of the development and function of an organism. In this process, cells that are no longer needed or that will be detrimental to an organism or tissue are disposed of in a neat and orderly manner; this prevents the development of an inflammatory response, which is often associated with Necrotic cell death. There are at least two broad pathways that lead to Apoptosis, an "Extrinsic" and an "Intrinsic" Pathway. In both pathways, signaling results in the activation of a family of Cys (Cysteine) Proteases, named Caspases that act in a proteolytic cascade to dismantle and remove the dying cell (Ref.1).

The Extrinsic pathway begins outside a cell, when conditions in the extracellular environment determine that a cell must die. Based on the triggering stimulus and nature of the components involved, at least two Apoptotic pathways can be differentiated; one involving Receptor Systems and the other triggered by Cytotoxic Stress. Receptor mediated pathways include those activated by Death ligands. Death Receptors are Cell surface Receptors that transmit Apoptotic signals initiated by specific ligands and play a central role in instructive Apoptosis. These receptors activate Death Caspases within seconds of ligand binding, causing an Apoptotic demise of the cell within hours. DRs (Death Receptors) belong to the superfamily of TNFR (Tumor Necrosis Factor Receptor), which are characterized by a Cys-rich Extracellular Domain and a homologous Intracellular Domain known as the Death Domain. Adapter-molecules like FADD (Fas-Associated via Death Domain), TRADD (Tumor Necrosis Factor Receptor-1-Associated Death Domain) or Daxx contain Death Domains so that they can interact with the DRs and transmit the Apoptotic signal to the death-machinery. The best-characterized Death Receptors are Fas and TNFR1 (Tumor Necrosis Factor Receptor-1). Other DRs include Apo2 and Apo3 (Ref.2).

FasL (Fas Ligand), a homotrimeric protein acts as ligand for Fas and causes oligomerization of its Receptor on binding. Associated with this is the clustering of the Death Domains and binding of cofactor FADD. The FADD protein binds via its DED (Death Effector Domain) motif to a homologous motif in Procaspase8. The complex of Fas, FADD and ProCaspase8 is called the DISC (Death Inducing Signaling Complex). The cofactor function of FADD, in turn, is blocked by interaction with the regulator FLIP (FLICE Inhibitory Protein). Upon recruitment by FADD, Procaspase8 oligomerization drives its activation through self-cleavage. Active Caspase8 then activates downstream Caspases (Caspase3 and 7), committing the cell to Apoptosis. Activated Caspase8 activates Caspase3 through two pathways. In the first pathway Caspase8 cleaves BID (Bcl2 Interacting Protein) and its COOH-terminal part translocates to Mitochondria where it triggers CytoC (Cytochrome-C) release. The released CytoC binds to APAF1 (Apoptotic Protease Activating Factor-1) together with dATP and Procaspase9 and activates Caspase9. The Caspase9 cleaves Procaspase3 and activates Caspase3. Another pathway is that Caspase8 cleaves Procaspase3 directly and activates it. The Caspase3 cleaves DNA fragmentation factor ICAD (Inhibitor of Caspase-Activated DNase) in a heterodimeric form consisting of CAD and cleaved ICAD. Cleaved ICAD dissociates from CAD, inducing oligomerization of CAD that has DNase activity. The active CAD oligomer causes the internucleosomal DNA fragmentation, which is an Apoptotic hallmark indicative of chromatin condensation (Ref.3). Recently, a nuclear pathway linked to Apoptosis has also been suggested. (ZIPK) ZIP Kinase triggers Apoptosis from nuclear PODs (PML (Promyelocytic Leukemia) Oncogenic Domains) and in collaboration with Daxx and Par-4 (Prostate Apoptosis Response Protein-4), mediates a novel nuclear pathway for Apoptosis. Another set of DRs Apo2 and Apo3 has been characterized that share a different death ligand, known as Apo2L (Apo2 Ligand), Apo3L(Apo3 Ligand). DISC complex formation and BID cleavage downstream of Apo2/Apo3 is similar to the Fas pathway (Ref.4).

In the case of TNFR1, various Death Domain-containing proteins can form distinct complexes in a temporal manner once the receptor is activated. A TNFR1 complex possessing the DD-containing protein TRADD, TRAF2 (TNF Receptor Associated Factor-2), CIAP1 (Cellular Inhibitor of Apoptosis-1), and the kinase RIP1 (Receptor-Interacting Protein-1) assembles at the Plasmamembrane within minutes after activation in order to recruit IKK (I-KappaB-Kinase) leading to NF-KappaB (Nuclear Factor-KappaB) activation and survival. In a second step, Complex II is formed after the TRADD-based complex dissociates from the receptor and recruits FADD and the initiator Caspase8. The balance of effects by complex I versus II rest with FLIP, an inhibitor of Caspase8. When Complex I NF-KappaB activation is sufficient, adequate FLIP is expressed to inhibit Caspase8 of complex II. Complex II can mediate Apoptosis only when Complex I-mediated NF-KappaB activation is insufficient (Ref.5). Besides DRs, Growth factors also influence Apoptosis via PI3K (Phosphatidylinositde-3 Kinase) and Akt (v-Akt Murine Thymoma Viral Oncogene Homolog) pathways. Growth factors binds to growth factor receptors and activates PI3K. Activation of PI3K pathways leads to Akt activation. Akt is very important in BAD (Bcl2-Antagonist of Cell Death) regulation, which is a proapoptotic member of Bcl2 (B-Cell Leukemia-2) family and is involved in Mitochondrial Apoptosis (Ref.6). PKC (Protein Kinase-C) may also play an important role in Apoptosis by activating p90RSKs (Ribosomal-S6 Kinases), which inhibits BAD.

In addition to Receptor-mediated Apoptosis, there is another pathway activated by various forms of Cellular Stress. Stress effects that can induce Apoptosis are Gamma- and UV radiation, treatment with cytotoxic drugs such as Actinomycin D and removal of cytokines. Stress induced Apoptosis occurs by a mechanism that involves altering mitochondrial permeability and subsequent CytoC release and formation of the Apoptosome, a catalytic multiprotein platform that activates Caspase9. Activated Caspase9 then cleaves Caspase3 resulting in downstream events involved in cell death. Release of CytoC is regulated by Bcl2 family proteins. Bcl2L (Bcl2-Like), BclXL (Bcl2 Related Protein Long Isoform) and other Anti-Apoptotic Bcl2 family members reside in the outer mitochondrial membrane and prevent CytoC release. BAX (Bcl2 Associated X-protein), BID (BH3 Interacting Death Domain) and BIM (Bcl2-Interacting Protein) are initially inactive and must translocate to mitochondria to induce Apoptosis, either by forming pores in mitochondria directly or by binding via BH3 domains to Bcl2, BclXL and Bfl1, and antagonizing these Anti-Apoptotic proteins. MMP (Mitochondrial Membrane Permeabilization) is clearly a pivotal event in the progression of Apoptosis in many systems. At least two mechanisms of MMP have been described. First mechanism proposes that VDAC (Voltage-Dependent Anion Channel), ANT (Adenine Nucleotide Transporter), PBR (Peripheral-type Benzodiazepine Receptor) and CypD (Cyclophilin-D) come together to form the PTPC (Permeability Transition Pore Complex). This pore complex may also associate with BAX, BAK1 (Bcl2 Antagonist Killer-1) or BIM, which accelerate channel opening or BclXL, which causes closure. According to the second mechanism BAX is released from its interaction with 14-3-3 and translocates from cytosol to mitochondria in response to diverse signals. Here it oligomerizes forming protein pores. Pore formation also takes place in conjunction with the BH3-only Bcl-2 family member BID upon proteolysis to tBID (Truncated BID). BAK1 is located at mitochondria and has similar pore forming properties to BAX, via its oligomerization and association with tBID. BID is activated by Caspase8-induced cleavage during DR signaling, whereas BIM is released from its association with microtubules (Ref.7).

Apoptosis can also occur via Intrinsic pathways. The Intrinsic Apoptosis pathway begins when an injury occurs within the cell. Intrinsic stresses such as Oncogenes, direct DNA damage, Hypoxia, and survival factor deprivation, can activate the Intrinsic Apoptotic pathway. p53 is a sensor of cellular stress and is a critical activator of the intrinsic pathway. The DNA checkpoints proteins, ATM (Ataxia Telangiectasia Mutated protein), and Chk2 (Checkpoints Factor-2) directly phosphorylate and stabilize p53 and inhibit MDM2 (Mouse Double Minute-2 Homolog) mediated ubiquitination of p53. MDM2 binds p53 and mediates the nuclear export. When bound to MDM2, p53 can no longer function as an activator of transcription. p53 initiates Apoptosis by transcriptionally activating proapoptotic Bcl2 family members and repressing antiapoptotic Bcl2 proteins and CIAPs. Other p53 targets include BAX, Noxa, PUMA (p53-Upregulated Modulator of Apoptosis) and the most recently identified, BID. p53 also transactivates other genes that may contribute to Apoptosis including PTEN (Phosphatase and Tensin Homolog Deleted On Chromosome-10), APAF1, Perp, p53AIP1 (p53-regulated Apoptosis-Inducing Protein-1), and genes that lead to increases in ROS (Reactive Oxygen Species). These ROS lead to generalized oxidative damage to all Mitochondrial components. Damage to Mitochondrial DNA disrupts Mitochondrial oxidative phosphorylation, contributing to a number of Human diseases (Ref.8).

Other proteins released from Damaged Mitochondria, SMAC (Second Mitochondria-Derived Activator of Caspase)/ Diablo, Arts and Omi/HTRA2 (High Temperature Requirement Protein-A2), counteract the effect of IAPs (Inhibitor of Apoptosis Proteins), which normally bind and prevent activation of Caspase3. The interaction between Bcl family members, IAPs, SMAC and Omi/HTRA2 is central to the intrinsic Apoptosis pathway. Recent studies demonstrated that another nuclease, EndoG (Endonuclease-G), is specifically activated by Apoptotic stimuli and is able to induce nucleosomal fragmentation of DNA independently of Caspase and DFF (DNA-Fragmentation Factor)/ CAD (Caspase-Activated DNAse). EndoG is a mitochondrion-specific nuclease that translocates to the nucleus and cleaves chromatin DNA during Apoptosis. Another protein, AIF (Apoptosis Inducing Factor) has also been attributed a role in Apoptosis, becoming active upon translocation from mitochondria to nuclei, where it initiates chromatin condensation and large-scale DNA fragmentation (Ref.9). Programmed cell death and its morphologic manifestation of Apoptosis is a conserved pathway that in its basic tenets appears operative in all metazoans. Apoptosis also operates in adult organisms to maintain normal cellular homeostasis. This is especially critical in long-lived mammals that must integrate multiple physiological as well as pathological death signals, which for example includes regulating the response to infectious agents. Gain and loss of function models of genes in the core Apoptotic pathway indicate that the violation of cellular homeostasis can be a primary pathogenic event that results in disease. Evidence indicates that insufficient Apoptosis can manifest as Cancer or Autoimmunity, while accelerated cell death is evident in Acute and Chronic Degenerative diseases, Immunodeficiency, and Infertility (Ref.10).

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Akt (v-Akt Murine Thymoma Viral Oncogene)/ PKB (Protein Kinase-B) is a Serine/threonine Kinase that is involved in mediating various biological responses, such as inhibition of Apoptosis and stimulation of cell proliferation. Three mammalian isoforms are currently known: Akt1/PKB- Alpha, Akt2/PKB-Beta and Akt3/PKB-Gamma. All three isoforms of Akt share a common structure of three domains. The N-terminus of the protein is a PH (Pleckstrin Homology) domain, which interacts with membrane lipid products such as PIP2 (Phosphatidylinositol-3,4-Bisphosphate) and PIP3 (Phosphatidylinositol-3,4,5-Triphosphate). The PH domain is approximately 100 amino acids and plays a role in recognition by upstream kinases and membrane translocation of Akt. The center region of the protein is the Kinase domain, which has high similarity to other kinases. This domain contains a conserved threonine residue, which needs to be phosphorylated in order to activate Akt. The approximately 40 amino acids at the C-terminus of the protein form a regulatory domain that contains a proline rich region and a hydrophobic motif with a conserved sequence of FXX (F/Y)(S/T)(Y/F). In mammals, this hydrophobic motif is FPQFSY. The serine or threonine residue in this motif must also be phosphorylated to activate Kinase activity of Akt. This is also a conserved residue (Ref.1).

Activation of Akt can begin with several events, mainly the binding of a Ligand to a Receptor in the cell membrane. Most common Ligands activating Akt include Growth factors, Cytokines, Mitogens and Hormones. Insulin and a variety of Growth factors bind to RTK (Receptor Tyrosine Kinase) and cause autophosphorylation of tyrosine residues on the intracellular domain of the receptor. PI3K (Phosphoinositol 3-Kinase) is recruited to the phosphotyrosine residues (consensus sequence pYXXM) via SH2 domains in the regulatory domain (p85), and is therefore targeted to the inner cell membrane. Binding of the p85 subunit of PI3K to the phosphorylated RTK leads to conformational changes in the catalytic domain of PI3K (p110) and consequent kinase activation. PI3K can be activated by Ras. Insulin can also activate PI3K via IRS1 (Insulin Receptor Substrate-1). GPCR (G-Protein-Coupled Receptor) also activates PI3K through GN-Beta (Guanine Nucleotide-Binding Protein-Beta) and GN-Gamma (Guanine Nucleotide-Binding Protein-Gamma) subunits of G-proteins. Cytokines can also activate PI3K via JAK1 (Janus Kinase-1). In B-Cells, PI3K is activated by BCR (B-Cell Receptor) via SYK (Spleen Tyrosine Kinase) and BCAP (B-Cell Receptor Associated Protein). PI3K then phosphorylates membrane bound PIP2 to generate PIP3. The binding of PIP3 to the PH domain anchors Akt to the plasma membrane and allows its phosphorylation and activation by PDK1 (Phosphoinositide-Dependent Kinase-1). DNA-PK, CDC37 (Cell Division Cycle-37), HSP90 (Heat Shock Protein-90KD) and PKCƒ{Beta (Protein Kinase-C-Beta) are also reported to phosphorylate Akt. Integrins also activates Akt via FAK (Focal Adhesion Kinase), Paxillin and ILK (Integrin-Linked Kinase). Akt can also be activated in response to a variety of cellular stress, such as heat shock, administration of ultra violet light, ischemia (a decrease in blood supply), hypoxia (oxygen deficiency), hypoglycemia (abnormally low level of glucose in the blood) and oxidative stress. The activity of Akt is negatively regulated by PTEN (Phosphatase and Tensin Homolog), SHIP (SH2-Containing Inositol Phosphatase) and CTMP (Carboxyl-Terminal Modulator Protein) (Ref.2, 3 & 4).

Akt inhibits apoptosis by phosphorylating the BAD component of the BAD/BclXL (Bcl2 Related Protein Long Isoform) complex. Phosphorylated BAD binds to 14-3-3 causing dissociation of the BAD/BclXL complex and allowing cell survival. Akt activates IKK, which ultimately leads to NF-KappaB activation and cell survival. Other direct targets of Akt are members of the FKHRL1 (Forkhead-Related Family of Mammalian Transcription Factor-1). In the presence of survival factors, Akt1 phosphorylates FKHRL1, leading to the association of FKHRL1 with 14-3-3 proteins and its retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 most likely triggers apoptosis by inducing the expression of genes that are critical for cell death, such as the TNFSF6 (Tumor Necrosis Factor Ligand Superfamily Member-6) gene. Another notable substrate of Akt is the death protease Caspase9. Phosphorylation of Caspase9 decreases apoptosis by directly inhibiting the protease activity. Akt also activates TERT (Telomere Reverse Transcriptase), which is responsible for telomere maintenance and DNA stability. Akt has been linked to angiogenesis, through the activation of eNOS, which influences long-term blood vessel growth. Akt can regulate several levels of Glucose metabolism. It enhances Glucose-uptake in Insulin-responsive tissues by inducing the expression of GLUT1 and GLUT3 and the translocation of GLUT4 to the plasma membrane; the GLUTs transport glucose into the cell. Akt also activates Glycogen synthesis by phosphorylating and inactivating GSK3, which leads to the activation of Glycogen Synthase and CyclinD1. Akt phosphorylates PDE3B on Ser273. This activates PDE3B and results in regulation of intracellular levels of cyclic nucleotides in response to Insulin. Akt induces glycolysis through the phosphorylation and activation PFK2, which in turn activates PFK1. These enzymes convert Fructose-6-Phosphate into Fructose-1, 6-Bisphosphate, a key step in Glucose metabolism. Akt may also be involved in activation of the nutrient-dependent Thr/Ser kinase, mTOR. Activation of mTOR results in the phosphorylation of ribosomal protein S6 kinase, p70S6K. Akt also phosphorylates the two tumor suppressor genes TSC1 and TSC2, which are negative regulators of the mTOR-S6K pathway. Phosphorylation of TSC1 and TSC2 results in suppression of their inhibitory activity and may also target the proteins for degradation. Activation of mTOR also results in phosphorylation and inactivation of eIF4EBP (Eukaryotic Initiation Factor-4E Binding Protein), an inhibitor of the translation initiation factor eIF4E. Nonphosphorylated PHASI binds to eIF4E (Eukaryotic Initiation Factor-4E) and inhibits protein synthesis. Akt also phosphorylates GAB2 (GRB2-Associated Binding Protein-2) on Ser159. Phosphorylation of Ser159 on Gab2 by Akt/PKB appears to negatively regulate GAB2 tyrosine phosphorylation by the ErbB receptor tyrosine kinases, although the underlying mechanism has not been solved (Ref.5 & 6).

The transcription factor CREB is directly phosphorylated at Ser133 by Akt. This causes an increased affinity of CREB for its co-activator protein, CRB (Crumbs). The heterodimer, now an active transcription factor, promotes transcription of genes that contain CREs (cAMP responsive elements) in their promoter, such as the anti-apoptotic genes Bcl2 and Mcl1. Akt also phosphorylates AR at two serine residues, Ser210 and Ser270, which causes a decrease in AR activity on the p21 promoter. In addition to causing cell cycle progression, this also results in apoptosis inhibition in certain cell types, through other actions of AR. YAP is another transcription factor that is phosphorylated by Akt, and is of importance because it does not contain an Akt consensus sequence. Akt phosphorylates Ser127 on YAP, which causes association with 14-3-3 proteins, nuclear export and cytoplasmic localization. Akt has also been shown to phosphorylate p21 directly, on Thr145. p21 is a member of the Cip/Kip family of CDK inhibitors that arrest the cell cycle and therefore limit cell proliferation. p21 can also promote cell cycle progression, via mediating the assembly and activity of cyclin D1-CDK4/6 complexes. P27 is another cyclin-dependent kinase inhibitor, of the Kip family. P27 inhibits CDK2 and CDK4/6 complexes, which is located in the nuclear localization signal. NLS targets protein to nucleus via nuclear import machinery, and phosphorylation in this region of p27 results in nuclear exclusion. 14-3-3 proteins bind phosphorylated p27 and cause active export from nucleus. Without p27 in the nucleus, the cyclin-CDK complexes form and promote cell cycle progression. Akt also phosphorylates MDM2. MDM2 is phosphorylated at many sites, only two of which have been identified. Ser166 is phosphorylated by Akt. Akt phosphorylation of MDM2 allows its entry into the nucleus where it targets p53 for degradation (Ref.7, 8, 9 & 10).

PRAS40 is a 40 kDa substrate of AKT. Activated AKT phosphorylates PRAS40 on threonine 246, enabling PRAS40 to bind to 14-3-3. AKT and PRAS40 are components of the PI3K pathway. This pathway plays a role in glucose uptake, cell growth, and apoptosis inhibition. The precise function of PRAS40 is not yet known; however, it has been hypothesized that PRAS40 interacts with SH3 and WW domain containing proteins, and may change the function of these proteins. Akt phosphorylates, both in vitro and in vivo, the GABA(A)R, the principal receptor mediating fast inhibitory synaptic transmission in the mammalian brain. Akt-mediated phosphorylation increases the number of GABA(A)Rs on the plasma membrane surface, thereby increasing the receptor-mediated synaptic transmission in neurons. XIAP is a physiological substrate of Akt. Akt interacts with and phosphorylates XIAP at serine 87. Phosphorylation of XIAP by Akt inhibits both its autoubiquitination and cisplatin-induced ubiquitination. These effects reduce XIAP degradation and the increased levels of XIAP are associated with decreased cisplatin-stimulated Caspase3 activity and programmed cell death. Htt is also a substrate of Akt and phosphorylation of Htt by Akt is crucial to mediate the neuroprotective effects of IGF1 (Insulin-Like Growth Factor-I). WNK1 is a physiologically relevant target of Insulin signaling through PI3K and Akt and functions as a negative regulator of Insulin-stimulated mitogenesis (Ref.11, 12 & 13). Akt also phosphorylates Ataxin1 and modulate neurodegeration.14-3-3 protein mediates the neurotoxicity of Ataxin1 by binding to and stabilizing Ataxin1, thereby slowing its normal degradation. Akt also decreases ASK1 kinase activity by phosphorylating a consensus Akt site at serine 83 of ASK1. Akt also interacts with the JIP1 (JNK Interacting Protein-1) scaffold and inhibits the ability of JIP1 to form active JNK signaling complexes. The binding of Akt to JIP1 is isoform specific; Akt1 but not Akt2 interacts with JIP1. Thus, Akt can inhibit one or more steps within the JNK signaling pathway, depending on the complement of components that form the functional JNK signaling module. Akt mediates PI3K-dependent p47Phox phosphorylation, which contributes to respiratory burst activity in human neutrophils. AKT impair Chk1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells. Akt and its upstream regulators are deregulated in a wide range of solid tumors and hematologic malignancies, hence the Akt pathway is considered a key determinant of biologic aggressiveness of these tumors, and a major potential target for novel anti-cancer therapies (Ref.14 & 15).

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Retinoic Acid, a lipophilic molecule and a metabolite of Vitamin-A (all-trans-Retinol), affects gene transcription and modulates a wide variety of biological processes like Cell Proliferation, Differentiation, including Apoptosis. Retinoic Acid mediated gene transcription depends on the rate of transport of Retinoic Acid to target cells and the timing of exposure of Retinoic Acid to RARs (Retinoic Acid Receptors) in the target tissues. The all-trans-Retinoic Acid, the Carboxylic Acid form of Vitamin-A is of biological significance since it has high circulating levels than other isomers of Retinoic Acid. The targets of all-trans-Retinoic Acid and RARs include a multitude of Structural genes, Oncogenes, Transcription Factors and Cytokines. Although biologically active ligands for the RARs also include 9-cis-Retinoic Acid among others, yet circulating levels of 9-cis-Retinoic Acid are much lower than those of all-trans-Retinoic Acid and the physiological significance of the isomerization all-trans-Retinoic Acid to 9-cis-Retinoic Acid and vice versa is yet to be ascertained (Ref.1). The all-trans-Retinoic acid is predominant under most physiological situations and explains all of the biological effects of Vitamin-A. The RARs are encoded by three separate genes with multiple isoforms-Alpha, Beta and Gamma, which are generated by alternative promoters and differential splicing. Like all NRs (Nuclear Receptors) RARs also have a conserved modular structure consisting of an AF-1 or A/B (Amino-Terminal Activating Factor-1 Transcriptional Activation) Domain; a zinc-finger DBD or C (DNA-Binding Domain); a CoR or D (Hinge/Corepressor Binding) Domain; a LBD or AF-2 or E (Ligand-Binding/Transcriptional Activation) Domain; and a variable F (Carboxyl-Terminal) Domain. In general, the RARs contain six regions from A-F. The DBD binds to the RARE (Retinoic Acid Response Element) region in the DNA. The RAREs consists of a DRs (Direct Repeats) of AGG/TTCA motif with a spacer region of (n)25. Vitamin-A in the liver is converted to all-trans-Retinoic Acid, diffuses easily to the target tissues through cellular membranes and is translocated to the RARs through CRABP (Cellular Retinoic Acid Binding Protein) (Ref.1 & 2).

The mechanism of all-trans-Retinoic Acid-induced Apoptosis is through Mitochondrial Dysfunction involving TRAIL (TNF-Related Apoptosis-Inducing Ligand) and it’s Death Receptors, the TRAILRs (TNF-Related Apoptosis-Inducing Ligand Receptors). all-trans-Retinoic Acid activate Ifns (Interferons) and both function synergistically to activate TRAILRs and Caspase8 (Cysteine Aspartate Specific Protease-8) that in turn induce the mitochondrial damage leading to the release of CytoC (Cytochrome-C). The TRAILRs contain the functional DDs (Death Domains), capable of inducing Apoptosis. Binding of TRAIL to TRAILRs and subsequent all-trans-Retinoic Acid-mediated activation leads to the recruitment of the Apoptosis Regulator FADD (Fas-Associated via Death Domain), which functions as a molecular bridge to Caspase8. Upon activation the TRAILRs indirectly bind to FADD via the GTP-binding protein DAP3 (Death-Associated Protein-3). Caspase8 cleaves BID (BH3 Interacting Domain Death Agonist) and the tBID (Truncated BID) translocates to mitochondria, inducing CytoC release. CytoC in association with APAF1 (Apoptotic Protease Activating Factor-1) activates Caspase9 (Apoptosis Related Cysteine Protease-9). Caspase9, in turn, causes the cleavage of proteins required for cellular viability, resulting in Apoptosis. Caspase9 also activates Caspase3 which directly cleaves downstream substrates like PARPs (Poly (ADP-Ribose) Polymerases) (Ref.3). Apoptosis by TRAIL and TRAILRs is controlled by FLIP (FLICE Inhibitory Protein), which inhibits the activation of Caspase8. Another mechanism of all-trans-Retinoic Acid induced Apoptosis requires Cytokine-mediated stimulation of PLA2 activity, resulting in the generation of excess Arachidonic Acid and this pathway is chiefly functional in the brain cells. Retinoic Acid functions as an important regulatory signaling molecule for Cell Growth, Differentiation and Neurodegeneration both during embryogenesis and in adult stage. Retinoic Acid induced Apoptosis through Death Receptors is a potentially promising approach for treatments of diseases like Schizophrenia, Alzheimer Disease and also for Cancer therapy (Ref.4 & 5).